The goal of this proposed research is to determine the chemical processes involved in the cytochrome P-450 catalyzed metabolism of halocarbon compounds. A thorough understanding of these processes is essential to the development of a broadly useful model for predicting the in vivo consequences of monooxygenase-mediated halocarbon metabolism, since minor metabolic pathways associated with mechanisms of low flux may have important toxicological implications. The chemical mechanisms of metabolism of three halocarbon structural classes, selected on the basis of their importance to human health and on their representative structural features which are incorporated in numerous compounds of toxicological relevance, will be determined via detailed in vitro studies. Central to these studies will be the examination of halide-dependent differences in metabolism, which occur upon substrate halogen substitution (that is, C-X substitution by F, Cl, Br and I) and the study of cytochrome P-450 isozyme dependent metabolic processes of these halocarbon classes. Complete metabolite profiles and kinetic parameters (Vmax, Km) for enzymatic transformation of each halocarbon will be integrated (possibly with additional data) to elucidate the chemical mechanisms and pathways of metabolism. The three structural classes to be examined are: 1,1,1-trichloroalkanes, as illustrated by 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT) and 1,1,1-trichloroethane (methylchloroform); specifically substituted dihalobenzenes; and 1,2-dihaloethanes. The nature of the chemically reactive intermediates formed in the enzymatic degradation of these organohalides, including the structures of products bound to protein and DNA, will be determined. In addition, studies will be directed at evaluating the generality and the role in inducing tissue damage of the reductive-oxygenation pathway associated with 1,1,1-trihaloalkane metabolism, at determining the effects on metabolism of the isoelectronic trichloromethyl and trifluoromethyl moieties, and at understanding nucleophile dependent electrophilic processes of anticipated metabolites of these substrates. Additional studies will be undertaken employing halo- (or dihalo-) oxepins to evaluate their propensities for macromolecule binding and employing halogenated small carbocyclic systems as sensitive probes of enzymatic mechanism.